Ovariectomy enhances and estrogen replacement inhibits the activity of bone marrow factors that stimulate prostaglandin production in cultured mouse calvariae.

Kawaguchi, Hiroshi; Pilbeam, Carol C.; Vargas, Socorro J.; Morse, Edward E.; Lorenzo, Joseph; Raisz, Lawrence G.

doi:10.1172/jci118066

Cited by 131 publications

(66 citation statements)

References 59 publications

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“…E2 modulates OC apoptosis and OC activity both directly (37,38) and indirectly via regulation of growth factors and prostaglandins (39,40). Conversely, inhibition of OC formation in vivo results, in part, from the ability of E2 to block the production of the pro-osteoclastogenic cytokines IL-1, IL-6, and TNF (9 -13).…”

Section: Discussionmentioning

confidence: 99%

Estrogen Decreases Osteoclast Formation by Down-regulating Receptor Activator of NF-κB Ligand (RANKL)-induced JNK Activation

Srivastava¹,

Toraldo²,

Weitzmann³

et al. 2001

Journal of Biological Chemistry

325

195

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The differentiation of cells of the monocytic lineage into mature osteoclasts (OC) is specifically induced by the tumor necrosis factor-related factor, RANKL (receptor activator of NF-B ligand; also known as OPGL, ODF, or TRANCE). Because inhibition of osteoclastogenesis is one of the main mechanisms by which estrogen (E2) prevents bone loss, it is likely that E2 may regulate either the production of, or the target cell responsiveness to RANKL. We found that E2 decreases the differentiation into OC of both murine bone marrow monocytes and RAW 264.7 cells, a monocytic line, by downregulating the activation of Jun N-terminal kinase 1 (JNK1). Diminished JNK1 activity results in decreased nuclear levels of the key osteoclastogenic transcription factors, c-Fos and c-Jun, and lower binding of these transcriptional inducers to DNA. Thus, one novel mechanism by which E2 down-regulates osteoclastogenesis is by decreasing the responsiveness of OC precursors to RANKL. The differentiation of osteoclast (OC)1 precursors of the monocytic lineage into mature OCs is induced specifically by simultaneous stimulation of bone marrow monocytes by two cytokines produced by bone marrow stromal cells, M-CSF (1-3) and a TNF-related factor known as receptor activator of NF-B ligand (RANKL) (also known as OPGL, TRANCE, or ODF) (4 -6). The formation of mature OCs is completely dependent on the presence of both RANKL and M-CSF, as demonstrated by the lack of OC development in mice lacking the expression of either factor (5,7,8).It is now recognized that inhibition of osteoclastogenesis is the main mechanism by which estrogen (E2) prevents bone loss (9, 10). Moreover, considerable evidence support the hypothesis that E2 down-regulates OC formation by blunting the production of IL-1, IL-6, and TNF (9 -13), cytokines that enhance the stromal cell production of RANKL and M-CSF (14 -17). Additional mechanisms that serve to explain the antiosteoclastogenic effects of E2 include the ability of sex steroids to stimulate the production of osteoprotegerin (OPG), a decoy RANKL receptor (18), and a direct repressive effect on the production of membrane-bound M-CSF (19,20).Despite the relevance of RANKL as an osteoclastogenic factor, and of the potent antiosteoclastogenic effect of E2, sex steroids have not been reported to regulate the production of RANKL. The lack of such regulation is consistent with the absence of both estrogen-responsive elements and binding sequences for E2-regulated transcription factors on the RANKL promoter (21).Binding of RANKL to its signaling receptor RANK results in the activation of Jun N-terminal kinase (JNK), a mitogenactivated protein kinase that increases the trans activation activity and the production of AP-1 transcription factors. We have recently reported that E2 down-regulates TNF-induced JNK activation in monocytic cells (22), and others have shown that OC formation is impaired in mice lacking the AP-1 factors c-Fos and c-Jun (23,24). These data prompted us to investigate the hypothesis that an additional mechani...

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Section: Discussionmentioning

confidence: 99%

Estrogen Decreases Osteoclast Formation by Down-regulating Receptor Activator of NF-κB Ligand (RANKL)-induced JNK Activation

Srivastava¹,

Toraldo²,

Weitzmann³

et al. 2001

Journal of Biological Chemistry

325

195

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“…Postmenopausal women lose bone due to a decrease in ovarian estrogen and an increase in bone resorption. Previous studies have shown that inflammatory cytokines such as IL-1 and PGE 2 may be involved in the mechanism of bone loss due to estrogen deficiency (7,8). In the present study, we examined the effects of nobiletin on bone resorption in vitro and on bone mass in ovariectomized (OVX) mice.…”

mentioning

confidence: 94%

“…Nobiletin (5,6,7,8,3′,4′-hexamethoxy flavone), a citrus polymethoxy flavonoid, is abundantly present in Citrus depressa and has several biological activities. Previous studies have shown that nobiletin exhibits anti-proliferative and apoptotic effects on various cancer cells (3) and inhibits inflammation pathways (4).…”

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confidence: 99%

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Nobiletin, a Polymethoxy Flavonoid, Suppresses Bone Resorption by Inhibiting NFκB-Dependent Prostaglandin E Synthesis in Osteoblasts and Prevents Bone Loss Due to Estrogen Deficiency

et al. 2011

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Abstract. Nobiletin, a polymethoxy flavonoid, prevents cancer and inflammation, but the roles of nobiletin in bone are unclear. We examined the effects of nobiletin on bone resorption in vitro and on bone mass in ovariectomized (OVX) mice in vivo. In vitro, nobiletin suppressed osteoclast formation and bone resorption induced by interleukin (IL)-1. Nobiletin suppressed the expression of cyclooxygenase-2, NFκB-dependent transcription, and prostaglandin E (PGE) production induced by IL-1 in osteoblasts. OVX mice showed severe bone loss in the femur by increased bone resorption due to estrogen deficiency, and nobiletin significantly restored the bone mass. Nobiletin could be beneficial to bone health in postmenopausal women.

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“…ovariectomized (oVX) animals are widely used as a model of osteoporosis due to estrogen deficiency. oVX mice exhibit severe bone loss in the femur, and inflammatory cytokines such as IL-1, IL-6, and PGE 2 may be involved in the mechanism of bone loss due to estrogen deficiency [7][8][9]14]. These cytokines are also involved in the inflammatory pathogenesis of periodontitis [11].…”

mentioning

confidence: 99%

The Correlation between Postmenopausal Osteoporosis and Inflammatory Periodontitis Regarding Bone Loss in Experimental Models

et al. 2012

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Abstract:We have invented a mouse model of periodontitis associated with alveolar bone loss induced by lipopolysaccharide. Ovariectomized (OVX) animals are widely used as a model for osteoporosis due to estrogen deficiency. To define the relationship between periodontitis and osteoporosis, we examined the influence of estrogen deficiency on the mouse alveolar bone mass. In OVX mice, bone loss was detected not only in the femur, but also in the alveolar bone, indicating that estrogen deficiency could induce resorption in alveolar bone. In experiments using a combination of osteoporosis and periodontitis models, OVX significantly enhanced the alveolar bone loss in the model of periodontitis. Therefore, postmenopausal osteoporosis may enhance the risk of periodontitis associated with inflammatory alveolar bone resorption.

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Ovariectomy enhances and estrogen replacement inhibits the activity of bone marrow factors that stimulate prostaglandin production in cultured mouse calvariae.

Cited by 131 publications

References 59 publications

Estrogen Decreases Osteoclast Formation by Down-regulating Receptor Activator of NF-κB Ligand (RANKL)-induced JNK Activation

Estrogen Decreases Osteoclast Formation by Down-regulating Receptor Activator of NF-κB Ligand (RANKL)-induced JNK Activation

Nobiletin, a Polymethoxy Flavonoid, Suppresses Bone Resorption by Inhibiting NFκB-Dependent Prostaglandin E Synthesis in Osteoblasts and Prevents Bone Loss Due to Estrogen Deficiency

The Correlation between Postmenopausal Osteoporosis and Inflammatory Periodontitis Regarding Bone Loss in Experimental Models

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